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Home , Acute liver failure, Liver failure, Organ dysfunction

Review articles -On-Chronic Failure

Verónica Pérez Guerra, MD1, Laura Ramírez Cardona, MD1, Oscar Mauricio Yepes Grajales, MD1, Juan David Vélez Rivera, MD2, Juan Ignacio Marín Zuluaga, MD3

1 Gastrohepatology Group of the School of at Abstract the Universidad de Antioquia in Medellín, Colombia 2 Internist and clinical hepatologist at IPS Universitaria Acute-on-chronic (ACLF) includes acute deterioration of liver functions in patients with either in Medellín, Colombia chronic de novo liver or already diagnosed . ACLF can be triggered by various hepatic 3 Internist - clinical hepatologist at the Hospital or extrahepatic precipitating factors. Among its clinical manifestations are renal dysfunction, hepatic encepha- Pablo Tobón Uribe and member of the Liver Transplant Group and Gastrohepatology Group lopathy, and multisystem organ failure. If not treated promptly translate the prognosis can be poor. Several at the Universidad de Antioquia, Professor at the scoring systems have been used to assess liver function and patient prognosis. Although multisystem organ Universidad Pontificia Bolivariana in Medellín, failure contraindicates , it remains the treatment of choice for this patients. Colombia

...... Keywords Received: 29-09-15 Acute-on-chronic liver failure, MARS, , hepatic , multisystem organ Accepted: 25-07-16 failure, immune paralysis, SOFA scores.

INTRODUCTION a high risk of death. Consequently, treatment and mana- gement of ACLF must be different from those appropriate Acute on chronic liver failure (ACLF) is an entity that has for decompensated . increasingly gained recognition but that still generates The Asian Pacific Association for the Study of the Liver controversy because of the lack of a consensus definition (APASL) issued on of the first definitions of ACLF as a since it covers acute deterioration of liver function in condition that develops in the context of a patient who may patients with known as well as newly or may not have been diagnosed with chronic liver disease diagnosed . (1) The clinical concept of ACLF and who suffers an acute insult manifested by and seeks to differentiate this condition from decompensated and which can become complicated within liver cirrhosis as shown in Figure 1. The hepatocellular the first four weeks by and/or encephalopathy. functioning of patients with liver cirrhosis slowly dete- (2) The European Association for the Study of the Liver riorates to a point at which decompensation occurs and (EASL) and the American Association for the Study of is manifested by complications associated with portal Liver Diseases (AASLD) define this entity as an acute dete- hypertension. At this point, the only treatment option rioration of a chronic underlying liver disease triggered by is liver transplantation. In contrast, patients with ACLF a precipitating event that leads to increased 3 month rates have more or less preserved liver functions but experience and multisystem organ failure. (3) a precipitating hepatic or extrahepatic event such as an Recently the European Association for the Study of the infection. Because of the exaggerated immune response, Liver Chronic Liver Failure (EASL CLIF) Consortium this quickly develops into multisystem organ failure with has defined acute on chronic liver failure based on the

260 © 2016 Asociaciones Colombianas de Gastroenterología, Endoscopia digestiva, Coloproctología y Hepatología Acute insult 100

Threshold for organ failure Liver function (%)

Irreversible failure Chronic decompensated cirrhosis

0 Months

Figure 1. The figure represents acute-on-chronic liver failure and differentiates it from chronic decompensated cirrhosis. The red line shows the progression of decompensated cirrhosis to organ failure at which point, due to the advanced stage of liver disease, opportunities to reverse liver disease are scarce, and the only treatment option is liver transplantation. The green line shows the development of ACLF in which sometimes good liver functioning deteriorates sharply due to a precipitating event which may lead to organ failure and a high risk of death. The patient may have advanced liver disease and appear to be stable but deteriorate sharply thanks to the precipitating event, and then progress to organ failure. This type of patient, in contrast those with advanced decompensated cirrhosis, has a potential for reversal and recovery to the state that existed prior to the precipitating event. Modified from Jalan R, Gines P, JC Olson, RP Mookerjee, Moreau R, Garcia-Tsao G, et al. Acute-on-chronic-liver-failure. J Hepatol. 2012; 57 (6): 1336-1348.

CANONIC study. The study analyzed development of her mortality rate than patients who had had prior acute according to the criteria of CLIF-SOFA decompensation. (6) (defined later in this text) in cirrhotic patients with acute decompensation which was defined as encephalopathy, DIAGNOSTIC CRITERIA ascites, and bacterial infec- tion. (4). This study demonstrated that ACLF patients The lack of diagnostic criteria is currently one of the biggest exist and have prognoses different from those of patients problems with ACLF. In 2013, the CANONIC study set with decompensated cirrhosis. a goal of establishing diagnostic criteria for ACLF based Due to the absence of a consensus definition, it has been on analysis of patients with organ failure as defined by the difficult to estimate the incidence and prevalence of ACLF, CLIF-SOFA score (Table 1) and the at 28-day mortality Nevertheless, the CANONIC study, which had a sample of rate as shown in Table 2. The study shows that most patients 1,343 patients hospitalized for acute decompensated cirr- with ACLF were young alcoholics who had associated hosis in 29 specialized centers in 8 European countries, had bacterial infections and who had higher white blood cell made it possible to calculate a prevalence of 31% for ACLF. counts and levels of C-reactive protein (CRP) than those The study also found that the mortality rate among ACLF found in patients without ACLF. The CLIF-SOFA score, patients was 34% in the first 28 days while it was only 1.9% which was higher in patients with ACLF, and leukocyte for patients without ACLF. (4) counts were independent predictors of mortality in these Other studies have estimated that 40% of patients with patients. Accordingly, in addition to organ failure and high advanced cirrhosis over a period of 5 years could develop mortality rates, diagnosis of ACLF should also consider age ACLF. (5) This same study identified that patients who at presentation, the precipitator of the event precipitant, had no prior episodes of acute decompensation had a hig- and any systemic inflammation which may develop. (4)

Acute-On-Chronic Liver Failure 261 Table 1. CLIF-SOFA score.

Organ/system 0 1 2 3 4 Liver ( mg/dL) <1.2 ≥1.2 to <2.0 ≥2.0 to <6.0 ≥6.0 to <12 ≥12.0 Kidney (Creatinine, mg/dL) <1.2 ≥1.2 to <2.0 ≥2.0 to <3.5 ≥3.5 to <5.0 ≥5.0 Cerebral (hepatic encephalopathy (HE stage) No HE I II III IV (INR) <1.1 ≥1.1 to <1.25 ≥1.25 to <1.5 ≥1.5 to <2.5 ≥2.5 or platelet count ≤20x109/L Circulation (MAP, mmHg) ≥70 <70 Dopamine ≤5 or Dopamine >5 or Dopamine >15 or Dobutamine or Terlipressin E ≤0.1 or NE ≤0.1 E >0.1 or NE >0.1 <400 >300 to ≤400 >200 to ≤300 >100 to ≤200 ≤100

PaO2/FiO2 o SpO2/FiO2 >512 >357 to ≤512 >214 to ≤357 >89 to ≤214 ≤89

The CLIF-SOFA score is a modification of the SOFA (Sequential Organ Failure Assessment) score developed for the CANONIC study because the SOFA score did not take into account specific characteristics of patients with cirrhosis. Like the SOFA score, the CLIF-SOFA score ranks organ failure from 0 to 4 in increasing order of organ/system disability. HE grades correspond to the West-Haven classification. Areas in bold indicate organ/system failure. HE: , INR: international normalized ratio, MAP: mean arterial pressure, E: epinephrine. NE:norepinephrine, PaO 2: arterial partial pressure, FiO 2: fraction of inspired oxygen, SpO2: pulse oximetry saturation. Modified from Reference 4.

Table 2. Definition of ACLF

EASL-CLIF CLIF/SOFA score definition of organ failure Liver failure defined by bilirubin of 12 mg/dL or higher. Renal failure defined by of 2 mg/dL or higher or by renal replacement therapy. Brain damage defined by West Haven encephalopathy the criteria Coagulopathy defined by INR of two or less in 20,000 Circulatory dysfunction defined as the need for vasoactive or inotropic drugs Pulmonary dysfunction defined as PF ration of less than 200 Definition of ACLF No ACLF: 3 groups 1. Patients without organ failure. 2. Patients with failure of only one organ (liver failure, circulatory, respiratory or coagulopathy) whose creatinine level is under 1.5 mg/dL and who do not have encephalopathy. 3. Patients who only have encephalopathy and whose creatinine level is below 1.5 mg/dL. * The mortality rate is 4.7% at 28 days and 14% at 90 days. ACLF 1: 3 groups 1. Patients with renal failure alone 2. Patients with one organ failure but without renal failure who have creatinine levels below 1.5 mg/dL and who do not have encephalopathy 3. Patients with encephalopathy whose creatinine levels are between 1.5 and 1.9 mg/dL. * The mortality rate is 22.1% at 28 days and 40.7% at 90 days. ACLF 2: Patients with failure of two organs * The mortality rate is 32% at 28 days and 52.3% at 90 days ACLF 3: Patients with failure of three or more organs * The mortality rate is 76.7% at 28 days and 79.1% at 90 days

Taken from Reference 9. ACLF: acute on chronic liver failure, CLIF/SOFA: Chronic Liver Failure-Sequential Organ Failure Assessment, INR: International Normalized Ratio, EASLD: European Association for the Study of the Liver.

PHYSIOPATHOLOGY infection and uncontrolled inflammatory responses chan- ges in ways that lead to damage characteristic of ACLF. The pathophysiology of ACLF has not yet been fully des- Something similar to the predisposition, infection, res- cribed, and much remains to be understood. However, ponse and organ failure (Piro) classification system what is known is that the immune response to injury, concept can be applied to description of the clinical mani-

262 Rev Col Gastroenterol / 31 (3) 2016 Review articles festations and pathophysiology of these patients (Figure as alcoholic , a flare-up of and 2). (3, 7) reactivation of chronic . (6) In the PIRO sepsis classification system, predisposition The PIRO system also takes into account immune res- is based on the severity and etiology of the underlying ponse. In recent years there has been a breakthrough in chronic liver disease. Any disease that leads to chronic liver the understanding of the pathophysiology of the transi- damage is classified as an underlying cause. These include tion from stabilized cirrhosis to the appearance of ACLF. , metabolic disease and not clas- Systemic inflammatory response syndrome (SIRS) in sified as steatosis. (2) In these cases the severity of liver which cytokines play an important role in inflammation disease is classified according to Child-Pugh and MELD is considered to be the starting point in this transition. (9) (Model for End Stage Liver Disease) scores. This syndrome results in liver damage and is characterized The appearance of ACLF in a patient who had compen- by inflammation, neutrophil dysfunction, , apopto- sated cirrhosis is the result of a precipitating factor which sis of liver cells, cholestasis and eventually fibrosis. (2, 8) corresponds to infection/inflammation in the PIRO sys- Nitric oxide (NO) production induced by inflammation tem. Infection and inflammation can directly increase liver and seems to explain the appearance of cir- damage, as in the cases of alcoholic or drug-induced hepatitis, culatory and renal disorders in ACLF. (10) In addition to , and thrombosis of the por- ACLF’s relation to proinflammatory, it has been linked to tal vein. It can also be extrahepatic, highlighting the trauma, the onset of encephalopathy through the modulating effect , variceal bleeding and infections (8). It is important it can have on concentrations of ammonium. (2) to note that, despite the variety of these precipitating events, Immune system dysfunction in ACLF resulting from the in a substantial proportion of patients (up to 40%) no cause inflammatory response of patients makes them more prone can be found that explains the appearance of ACLF. (3) to infections which in turn induce inflammation, resulting Some authors have proposed, a classification of ACLF into in a vicious circle. (11) Infections have been associated with Type I and Type II based on precipitating factors. In Type I, increased morbidity and mortality of patients with ACLF. The the precipitant is a extrahepatic event, most commonly infec- mortality rate of patients with cirrhosis who develop severe tions. In Type II, the precipitating event is intrahepatic such bacterial infections accompanied by septic is somewhere

PIRO concept of acute on chronic liver failure Evaluation Intervention (ACLF)

Early diagnosis Etiology Severity of Risk Staging Predisposition Child-Pugh Score Cirrhosis Preventative strategies MELD score (biomarkers) (New Interventions)

Hepatic Rapid treatment of event Injury Precipitating event Extrahepatic Attention blocks (Therapies) (New Interventions)

Inflammation Vigilance and Response Inflammation Immune System Failure Goal oriented approach (Biomarkers) (Biomarkers and New Interventions)

SOFA ICU, Organ support Organ Organ Failure APACHE Liver Transplantation (Biomarkers) (Liver support, stem cell treatment)

Figure 2. PIRO concept of acute-on-chronic liver failure (ACLF). In patients with ACLF, the PIRO concept is useful for defining pathogenesis and prognosis. Predisposition is determined by severity of underlying disease. The lesion is defined by type and by severity of the precipitating event. The response is defined by the host’s reaction to injury which determines the severity of inflammation and risk of infection. Organs are categorized by the extent of organ failure. The location of patients within these categories allows definition of interventions and helps identify the prognosis at different levels. Modified from Jalan R, Gines P, JC Olson, RP Mookerjee, Moreau R, Garcia-Tsao G, et al. Acute-on-chronic-liver-failure. J Hepatol. 2012; 57 (6): 1336-1348.

Acute-On-Chronic Liver Failure 263 between 60% and 100%. (12-14) In cirrhotic patients, sepsis is chronic liver failure. The problem is that tests are difficult to an important precipitating factor for significant comorbidities interpret in patients with cirrhosis since they may be affected including hepatic encephalopathy and bleeding varices which by the underlying liver disease which makes diagnosis and have significant impacts on mortality. (3) determination of prognosis based on the scores difficult. (19) Various authors have shown that immune deficiencies in ACLF are comparable to those of patients with sepsis. Renal Dysfunction The clinical pictures are very similar: shock is progressi- vely evidenced by and multiple organ failure. Following the liver, the organ that fails most frequently (15) The most important immune deficiency is functional is the kidney. Kidney damage can be classified into four failure of neutrophils which decreases phagocytic capacity types: pre-renal, parenchymal kidney disease, renal damage and causes oxidative stress which has been linked to increa- secondary to medication, and hepatorenal syndrome. The sed risk of infection and the subsequent development of prerenal component is the cause of 68% of cases, followed organ failure and death. (16) Other cells of innate immu- by parenchymal kidney disease which causes 32% of cases. nity, such as monocytes and natural killer (NK) cells are (20) Renal failure associated with liver cirrhosis is defined as also affected. Cells of acquired immunity area also affected creatinine levels over 1.5 mg/dL. International Ascites Club as they fail to proliferate and apoptosis increases. (3) criteria guide diagnosis of hepatorenal syndrome and diffe- rentiate it from other causes of renal failure (Table 3). (21) Role of Cytokines Table 3. Criteria for hepatorenal syndrome. High levels of TNF-α, sTNF-αR1, sTNF-αR2, IL-2, IL-2R, IL-4, IL-6, IL-8, IL-10 and IFN-γ have been described Cirrhosis and ascites in ACLF. (2, 17) These high levels may result from endo- Serum creatinine greater than 1.5 mg/dL toxemia which stimulates production or release of necro- No improvement in serum creatinine (decrease to 1.5 mg/dL or tic and which are not removed due to liver more) after at least 48 hours of withdrawal from diuretic and volume failure. Although TNF-α induces apoptosis of hepatocytes, expansion with (recommended dosage: 1g/kg body weight per day to a maximum of 100 g albumin/day). it has been found that this cytokine, along with IL-6, can Absence of shock promote regeneration and proliferation of hepatocytes through the production of acute phase reactants which Patient is not receiving, and has not recently received, nephrotoxic drugs. have the effect of countering apoptosis. (18) Because SIRS, Absence of parenchymal kidney disease indicated by proteinuria> 500 the transition from compensated cirrhosis to liver failure, mg/day, hematuria > 50 RBC/HPF) and abnormal renal ultrasound. is mediated by these cytokines, inhibition of inflammatory responses that these cytokines induce has been presented HPF: high power field. Taken from the Reference 17. as an alternative for reducing morbidity and mortality in patients with ACLF. (2) There are two types of hepatorenal syndrome. Type Multiple organ dysfunction in the PIRO system, regardless I evolves more rapidly and is characterized by baseline of the cause of the underlying liver disease, is what determi- serum creatinine increases of more than 100% to values nes the prognoses of patients with ACLF. As inflammatory over 2.5 mg/dL in less than two weeks. Its appearance is disorders progress they ultimately lead to alteration of usually related to a precipitating factor, the most common macrocirculation, microcirculation, endothelial dysfunction of which is spontaneous bacterial (SBP). (22) and organ failure. The multiple hit and critical mass hypothe- It is associated with a rapid deterioration of liver function sis proposes that multiple injuries are what lead to organ and encephalopathy, and its prognosis is poor. Type II is damage. Studies have shown that patients who had been hos- more stable and evolves more slowly. It is characterized by pitalized in the six months prior to an episode have higher creatinine levels over 1.5 mg/dL. It occurs spontaneously mortality than patients who had not been hospitalized with in most cases and has a better prognosis, but it does indi- mortality rates of 78% versus 34%. (10) cate progression of liver disease. (1) in cirrhotic patients produces splan- CLINICAL MANIFESTATIONS chnic vasodilation which leads to low blood pressure. This in turn activates regulatory mechanisms such as antidiuretic Liver Dysfunction hormone (ADH) from the renin-angiotensin system and the sympathetic nervous system leading to the occurrence Coagulopathy and hyperbilirubinemia, which manifests as of ascites. (23) Finally, hepatorenal syndrome develops as jaundice, are fundamental criteria for diagnosis of acute on the result of vasoconstriction of the renal vessels. (1)

264 Rev Col Gastroenterol / 31 (3) 2016 Review articles The development of renal failure depends largely on rapid therapeutic approach in these cases. If patients undergo and effective diagnosis. Monitoring of blood pressure and transplantation without prior resolution of hepatorenal urine output should be continuous when patients admitted syndrome, their prognoses are poorer. (26) with complications of cirrhosis are admitted to emergency services. A complete physical examination and laboratory Hepatic Encephalopathy tests including serum creatinine are vital. (1) When there are signs of hemodynamic instability and renal failure, it is Acute or chronic liver disease can lead to different neuro- necessary to control urine output and central venous pres- logical manifestations which together are called hepatic sure through placement of a urinary and a central encephalopathy. These manifestations are mediated by two catheter. Since ascites, and are results events: the portosystemic shunting and liver failure. (27) of the expansion of extracellular volume in hepatic impair- The most common pathophysiological process is based ment, fluid intake and sodium levels must be reduced. (1) on passage of unaltered nitrogenous substances such as Given the marked in these cases, the first from the liver through the systemic. There may treatment option has been considered terlipressin and also be alterations in systems that inhibit neurotransmis- albumin which has managed to reverse this syndrome in sion (GABAergic, glutamatergic, and/or serotoninergic 40% to 70% of patients thus improving prognoses in these agents), changes in blood flow, and changes in brain per- cases. The treatment scheme should be adjusted according meability to different products which cause changes in the to the patient’s progress. form and function of and affect cerebral ammo- • Initially, low doses of intravenous terlipressin (0.5-1 mg nium metabolism. (29) every 4 hours) should be administered. Dosage should The classification of HE is based on the West Haven cri- remain low during the first 48 hours. Simultaneously, teria which takes into account the neurological manifesta- 1 g/kg of albumin should be slowly administered over tions of patients (Table 4). (30) 24 hours. The diagnosis is eminently clinical and is based on exclu- • According to the patient’s blood volume, doses of albumin sion of other entities that affect functioning of the central between 20 and 40 g/day should then be administered. nervous system (CNS) such as head injuries, poisoning, If there is fluid overload (central venous pressure greater drugs overdoses, epilepsy, strokes, CNS infections, uremia, than 15 mm Hg), albumin should be discontinued. hypercapnia, and psychiatric disorders. (31) After establis- • Serum creatinine levels must be constantly monitored hing the diagnosis, it is necessary to determine the precipi- to determine response to treatment. If the decline in tating factors such as gastrointestinal bleeding, CNS inhibi- creatinine in the first 72 hours is less than the expec- tory drugs, , SBP, impaired renal function and ted decrease of 25% or more compared to baseline, the electrolyte balance in order to begin treatment rapidly and dose of terlipressin should be increased to the maxi- in the best way. mum allowable of 2 mg every 4 hours. • It should be noted that the treatment has no definite Table 4. West Haven Classification of Hepatic Encephalopathy time limit for discontinuation. The range reported in various studies is s from seven to 14 days or the Grade 0 Changes in personality or behavior not detectable. treatment is discontinued when creatinine levels fall absent below 1.5 mg/day. Terlipressin is contraindicated in Grade 1 Attention dysfunction, irritability, depression, personality patients with heart conditions. It is important to moni- changes, hypersomnia, insomnia. Asterixis evident. tor vital signs and constantly look for signs of peripheral Grade 2 Drowsiness, apathy, behavior changes, deficient memory ischemia. (24) and computing power. Asterixis evident. Grade 3 Confusion, disorientation, stupor, mental and physical slowness. Asterixis may not be present. Other vasoconstrictors including midodrine have been tested for treatment of hepatorenal syndrome, but they not Grade 4 (Use the to evaluate). are yet recommended for therapeutic management because there has been insufficient study of their usefulness for cli- These factors can be found in up to 80% of patients with nical treatment of disease. (25) Another option is norepi- HE. (1, 32) nephrine. Studies have shown that its effectiveness is equi- Therapeutic management of HE depends on its grade. valent to terlipressin for management of both Type 1 and If a patient has HE Grade II to IV, protein intake should Type 2 hepatorenal syndrome, but that it is less expensive. not be restricted as this may complicate the metabolism of The aim of reversing hepatorenal syndrome is to enable ammonium ion to muscles. At all levels of encephalopathy the patient to undergo transplantation which is the final adequate nutrition must be ensured. (32, 33)

Acute-On-Chronic Liver Failure 265 Given that the consciousness of these patients is impai- Multiple Organ Failure red, and hence their eating habits are poor, nasogastric tubes are usually used for both feeding and administration As defined by the EASL and the AASLD, organ failure plays of . Intubation of HE patients is only indicated a central role in ACLF, and the hypothesis that organ failure for those who are in a coma (HE grade IV) in order to behaves differently in patients with ACLF than in patients prevent aspiration. (1) Identification of the precipitating with decompensated chronic liver cirrhosis arises. The deve- factor is key because may allow reversal and avoid more lopment of multiple organ failure is characterized by signifi- complex states of altered consciousness. When the precipi- cant alterations in systemic and hepatic and tating factor is not known with certainty, general measures worsening liver function. Bacterial translocation plays an for suspected clinical events are taken. For example, if an important role in the transition from compensated cirrhosis infection is suspected, should be started empi- to decompensated cirrhosis, and together with the bacterial rically. Similarly, when there are electrolyte imbalances or infection is the most common precipitant of deterioration impaired renal function, administration of diuretics should through the systemic inflammatory response. (38) be discontinued. (32) Currently, prognostic factors that determine the outcome Nonabsorbable disaccharides (lactulose) should be of patients with cirrhosis and multi-organ failure are under administered to lower levels of ammonia, one of the most review, (39) but it seems that Child-Pugh and MELD sco- toxic molecules that triggers HE. These disaccharides cut ring systems are less effective and accurate than the SOFA fatty acid chains with the help of the colonic bacterial flora, system. (40) thus achieving an acidification of the medium and increa- It has been shown that early intervention can prevent the sing hydrogen which favors the conversion of ammonium occurrence of multisystem organ failure if the precipitating into the nonabsorbable ammonia molecule. Administration factors are attacked aggressively. may be oral or rectal (enemas). (34, 35) The goal of treatment is for the patient to have two to MANAGEMENT AND TREATMENT three soft stools daily. The oral dose is 20 mL lactitol every 8 hours. If administration is rectal (rectal probe balloon), Aside from the aforementioned support measures for the the dose should be 300 mL of lactulose in 700 mL of management of major complications, there is no specific water, or 200g of lactitol diluted in one 1 liter of water. treatment to improve the probability that these patients If the number of stools continues to increase, adminis- will survive. Artificial liver support systems appear to be tration should be discontinued or the dosage should be an attractive strategy for management of ACLF. (41) They decreased. (1, 32). Another option for reducing ammo- have the basic action mechanism of performing nium levels is to inhibit proteolytic flora of the colon with with albumin because the primary toxic substances that drugs such as neomycin, paromomycin, metronidazole, accumulate in the presence of hepatocellular insufficiency rifaximin and amoxicillin clavulanate. (36) Nevertheless, are not water-soluble but remain bound to proteins. Among rifaximin is the only drug that has been shown to control these substances are bile acids, bilirubin, prostacyclin, acute encephalopathy and chronic symptoms. Rifaximin nitric oxide, fatty acids, , ammonium lactate and is administered in doses of 400 mg every 8 hours either proinflammatory cytokines. (42) orally or through a nasogastric tube. (37) In addition to reducing levels of proinflammatory cyto- Drugs such as L-ornithine, L-aspartate, sodium ben- kines TNF-α, IL-10, and IL-6 that can perpetuate liver zoate and zinc that affect the urea cycle have also been damage and extend inflammatory cascade to other organs, tried. Recent treatment guidelines for encephalopathy have the aim of this process is to detoxify the body of compo- shown their effectiveness for controlling acute encephalo- nents of liver and kidney metabolism. (43). It has been pathy, but there is little evidence about the long-term use of shown that these toxic components trigger cell damage these drugs. (32) mediated by apoptosis and necrosis which leads to the release of more toxins which ultimately affect the renal, Cardiac Dysfunction circulatory and central nervous systems with consequent multisystem organ failure. (2) Artificial liver support sys- While patients with decompensated cirrhosis maintain high tems seek to reduce the time for patient recovery and thus , patients with ACLF do not: cardiac output serve as a bridge to liver transplantation which is the only falls, and there may be systolic and/or diastolic . effective treatment to date. (44) This presentation is associated with increased mortality, The most common system is the Molecular Adsorbent especially when there is also renal dysfunction. (3) Recirculation System (MARS) which uses exogenous albu-

266 Rev Col Gastroenterol / 31 (3) 2016 Review articles min at 10% to 20% and a perforated polysulfone membrane Another study of 238 patients by Finkenstedt and collea- with a 2.2 m2 absorption surface and pores that do not gues evaluated acute-on-chronic liver failure in 94 patients allow passage of substances with molecular weights larger who were evaluated for liver transplantation. Seventy-one than 50 kD. The technique involves conventional low-flow patients were placed on the transplant list, but only 33 dialysis in which bicarbonate is incorporated to maintain patients were able to undergo transplantation. The morta- fluid and electrolyte balance. (45-47) lity rate was 54%. The one-year survival rate was 84%,and ​​ Some studies have demonstrated the ability of MARS to the five-year survival rate was 82%, (55). Bahirwani and decrease amounts of vasoactive substances such as angio- colleagues described a retrospective cohort of 332 patients tensin, aldosterone, renin, norepinephrine and vasopressin who underwent liver transplantations because of ACLF. which results in improvement of hemodynamic patterns. Their objective was to assess whether acute-on-chronic Studies have also found improvement in portal pressure liver failure was associated with worse than usual outcomes and increased liver, renal and cerebral blood flow. (48, after transplantation. There were no statistically significant 49) However, other studies indicate no significant impro- differences in mortality, renal dysfunction, recurrence of vement of clinical parameters and transplant-free survival cirrhosis or retransplantation between these patients and compared with standard medical management. (50, 51) It patients who underwent transplantation for other reasons is argued that improvements in hepatorenal syndrome and which indicates that there are no differences in prognoses hepatic encephalopathy are not enough to make a signifi- with patients with decompensated cirrhosis. (56) cant difference in survival compared to standard medical These studies conclude that liver transplantation is the management’s achievements. Nevertheless, more study option for improving survival of ACLF patients; it is a safe is needed to determine some characteristics of the use of option with high one-year and five-year survival rates a year. MARS such as frequency of treatment. (41) The most To avoid futile procedures, what remains to be determi- widely accepted use is for earliest response to the compli- ned is the optimal moment for patients to undergo trans- cation of hepatic encephalopathy. (52) plantation and which patients are most likely to benefit. Use of MARS is contraindicated in patients with severe coagulopathy because there is a slight decrease in platelets CONCLUSION during the procedure and because anticoagulation is requi- red during the dialysis process. 53) The most important ACFL is a syndrome affecting a group of patients with chro- adverse effect has been bleeding, but frequent infections have nic liver failure. They develop multiple organ dysfunction also been reported. To reduce the risk of infection, concomi- that impacts morbidity and mortality. ACFL is under inves- tant use of antibiotics is recommended. Other side effects tigation, but many questions remain, especially regarding include disseminated intravascular coagulation, , definitions and its pathophysiology. Nevertheless, it clearly fever, sepsis, hypotension and renal insufficiency. (42) has prognoses that differ from those of Artificial liver support systems such as MARS are only and patients with decompensated cirrhosis. This, added bridges to liver transplantation. At present there is little data to the heterogeneity of current definitions, makes ACFL regarding outcomes of patients with ACLF, so it is difficult an entity under construction and in which there are many to determine exactly at what point in the process is best for areas of uncertainty. Currently, treatment aims at mitigating patients to undergo transplantation. This is especially true organ dysfunction. Liver transplantation is the option that given the multiple complications that patients in this state confers improved survival in the short and long terms. The can have. Potential complications include hemodynamic future is focused on defining the moment patients should instability, need for high doses of inotropic agents, high undergo transplantation time, determination of which , and low cerebral perfusion pressure. patients are candidates for this measure, and on understan- Bin-Wei and colleagues have described 100 patients who ding ACLF’s pathophysiology to allow improved diagnosis underwent transplantation because of ACLF. Transplant and management strategies. patients had high MELD scores (32 on average), high levels of bilirubin, and high INRs, and SOFA scores of nine or REFERENCES higher. The one-year survival rate of these patients was 76.8%, their three-year survival rate was 75.6%, and their 1. Arvaniti V, D’Amico G, Fede G, Manousou P, Tsochatzis E, five-year survival rate was 74.1%. Overall mortality was Pleguezuelo M, et al. Infections in patients with cirrhosis 20%. 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